The biological significance of DNA content

人类基因组中的蛋白质编码序列只有25,000个，占总DNA含量的不到2%。基因组的绝大多数非编码的生物学意义仍然是个谜。今天，涉及序列比较的主要举措(例如，ENCODE)正在进行中，以确定所谓的“垃圾DNA”部分是否以及以何种方式可能在调节或其他能力方面起作用。更广泛地说，人们已经知道基因组总DNA含量在生物表型方面是非中性的，这已经有50多年的历史了。事实上，基因组大小已经被报道与动物和植物的各种特征相关，包括身体大小、代谢率和发育速度。这些关系被认为源于基因组大小、细胞大小和细胞分裂率之间的因果联系，但到目前为止，这一点还没有被详细解决。这里提出的研究将利用现代技术来解决这个长期存在的问题，并将重点放在三个不同但相互关联的研究系统上。第一个是比较不同组织和分类群的基因组大小和细胞大小，以评估基因组大小-细胞大小关系的普遍性。这将伴随着旨在测试通过影响细胞周期调节将基因组大小与细胞大小联系起来的机械假说的实验工作。第二项研究包括对脊椎动物的研究，这些脊椎动物的红细胞不含核，但DNA含量对细胞大小的影响仍然存在。第三部分将研究在某些节肢动物组织中发生的大规模基因组倍增的基础和后果。总而言之，这三项研究将使大规模基因组学中的几个关键问题首次得到回答，并将直接有助于我理解动物基因组中非编码DNA的起源、特征和生物学相关性的长期目标。除了为学生提供特殊的培训机会外，该计划还将产生对在一系列生物学学科工作的生物学家具有实际意义的数据和方法。

Protein coding sequences in the human genome number only ~25,000 and constitute less than 2% of the total DNA content. The biological significance of the vast non-coding majority of the genome has remained enigmatic. Today, major initiatives involving sequence comparisons (e.g., ENCODE) are underway to determine whether and in what way portions of so-called "junk DNA" may be functional in regulatory or other capacities. More broadly, it has been known for more than 50 years that total genomic DNA content is non-neutral with respect to organism phenotypes. Indeed, genome size has been reported to correlate with a variety of traits in animals and plants, including body size, metabolic rate, and developmental rate. These relationships are thought to derive from causal links between genome size, cell size, and cell division rate, but to date this has not been addressed in detail. The research proposed here will bring modern technologies to bear on this long-standing question, and will focus on three different but interrelated study systems. The first involves comparisons of genome sizes and cell sizes from a diverse array of tissues and taxa in order to assess the universality of the genome size-cell size relationship. This will be accompanied by experimental work aimed at testing mechanistic hypotheses linking genome size to cell size via influences on cell cycle regulation. The second includes a study of vertebrates whose red blood cells contain no nuclei, but among whom the effects of DNA content on cell size persist. The third will examine the basis and consequences of the massive genome multiplication that occurs within certain arthropod tissues. In total, these three studies will allow several critical questions in large-scale genomics to be answered for the first time, and will contribute directly to my long-term goal of understanding the origins, characteristics, and biological relevance of non-coding DNA within animal genomes. This program will generate both data and methods of practical significance to biologists working in a range of biological disciplines, in addition to providing exceptional opportunities for student training.